1. Field of the Invention
The present invention relates to a temperature and pH-sensitive block copolymer, a method of preparing the block copolymer and a drug delivery using the block copolymer, and more particularly, to a multiblock copolymer, which has excellent gel strength and is sensitive to pH as well as temperature, a method of preparing the multiblock copolymer and a drug delivery system using the multiblock copolymer.
2. Description of the Related Art
Biocompatible polymers are used in various medical treatments, such as diagnosis and therapy, and are used as part of the human body. Recently, drug delivery systems that control a sol-gel transition phenomenon by changing the structure of molecules using biodegradable polymers or amphiphilic polymers, having both hydrophobic groups and hydrophilic groups, or by forming hydrogels using block copolymers, have been actively researched.
It is disclosed in U.S. Pat. No. 4,942,035 that the problem in which poly(ethylene glycol) and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer are not degraded in the body is improved using a copolymer of poly(alkylene glycol), which is a hydrophilic polymer, polylactide or polyglycolide, which is a biodegradable polyester polymer, and polycaprolactone.
Further, U.S. Pat. No. 5,476,909 discloses an A-B-A type triblock copolymer, which is a biodegradable polyester polymer, wherein the hydrophobic block (A) is limited to polylactide (PLA), polyglycolide (PGA) and copolymers thereof, and the hydrophilic block (B) is also limited to poly(ethylene glycol) (PEG) and derivatives thereof.
Further, U.S. Pat. No. 6,004,573 discloses an amphiphilic block copolymer, which is a biodegradable low molecular weight triblock copolymer comprising a hydrophobic block composed of a copolymer of PLA and PGA and a hydrophilic block composed of PEG. Due to the increase in the amount of the hydrophobic portion thereof, the copolymer remains in a sol state, which is a clear liquid state, at a temperature of 5° C. to 25° C., and is then automatically changed into a gel phase, that is, a water-containing semi-solid hydrogel phase, by the body temperature (37° C.) when it is put into the body. Therefore, the copolymer continuously remains in a gel phase and exhibits insolubility, and thermal gelation is induced reversibly, and thus the copolymer can be used as a drug delivery system for slowly discharging a drug present in a gel.
Further, U.S. Patent Application Publication No. 2006-0239961 discloses a water soluble, nonpeptidic polymer comprising two or more alkylene oxide-based oligomers linked together by hydrolytically degradable linkages such as ester linkage. Here, the polymer is an amphiphilic triblock copolymer having a central propylene oxide block or a butylene oxide block positioned between two ethylene oxide blocks. The polymer can be hydrolytically degraded into oligomers under physiological conditions. In aqueous media, the polymer preferably forms thermally reversible, hydrolytically degradable hydrogels that can be used, for example, for drug delivery and related biomedical applications.
However, since such block copolymers have sol-gel transition characteristics sensitive only to temperature, there are problems in that the temperature of an injection needle is the same as that of the body while they are injected into the body, so that the block copolymers are gelated before they are completely injected into the body, thereby clogging the injection needle.
Further, the above technologies are problematic in that the gel strength of the hydrogel is not sufficient even when a drug-containing hydrogel is completely injected into the human body, and a drug is excessively discharged due to the biodegradation of the hydrogel at the early stage of the injection of the drug, and thus the discharge of the drug cannot be controlled for a long time.
In addition, although it has been reported that block copolymers having a hydrophobic block including PLA, PGA, polycaprolactone (PCL) or the like are sensitive to pH, in reality, they are not suitable for practical use because they are not sensitive enough for use at the pH of the body.
Meanwhile, Korean Unexamined Patent Publication No. 2000-0012970 discloses a pH sensitive polymer comprising a sulfonamide group and a method of preparing the same. Here, in the case of a block copolymer hydrogel formed by random-copolymerizing sulfonamide monomers with dimethylacrylamide or isopropylacrylamide, since the pH sensitive component of the block copolymer hydrogel has anionic charges, the block copolymer hydrogel is largely used as a drug delivery system for delivering drugs having cationic charges, the use of which is limited.
Further, Korean Registered Patent No. 665672 discloses a method of preparing a block copolymer hydrogel using poly(β-amino ester) as a pH sensitive component. It is disclosed in this document that a block copolymer sensitive to pH as well as temperature is synthesized, and the synthesized block copolymer is gelated at a pH ranging from 7.0 to 7.4, which is similar to that in the body, and is solated outside the pH range, so that an injection needle is not clogged at the time of injecting the block copolymer into the body, whereas the injection needle is clogged at the time of injecting the conventional temperature-sensitive hydrogel thereinto, thereby safely forming gel in the body. Therefore, it can be seen that the prepared block copolymer can be used as a drug delivery system for discharging drugs targeted at specific temperature and pH.
However, the hydrogel is problematic in that, since its main chain has an ester bond and an amide bond, the gel strength thereof is rapidly decreased at the time of injection of the hydrogel into the body, and thus the use of the hydrogel as a drug delivery system for discharging drugs for a long time is limited.